Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1β (IL-1β) in astrocyte cultures

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of HIF-1 alpha and HIF-1 beta subunits and involved in the regulation of gene expression in adaptive response to hypoxia. This study reports that the inflammatory cytokine interleukin-1 beta (IL-1 beta) shares common features of other known HIF-1 alpha-regulated genes. Both human and mouse IL-1 beta genes carry multiple HIF-1-binding sites in their promoter regions and are up-regulated by hypoxia and CoCl2 in human and mouse astrocytes in parallel with up-regulation of HIF-1 alpha mRNA and protein. Inhibition of HIF-1 alpha degradation by proteasome inhibitor, MG- 132, potentiated hypoxia-induced IL-1 beta release from human astrocytes, and this response was blocked in the presence of CdCl2. Mouse astrocytes with Hif1 alpha(+/-) genotype demonstrated attenuated up-regulation of both HIF-1 alpha and IL-1 beta by hypoxia and CoCl2. Mutation of HIF-1-binding sites in the IL-1 beta promoter abolished hypoxia-induced transactivation of the reporter gene transfected into human astrocytes. Similarly, HIF-1 binding decoy oligonuleotide transfected into astrocytes inhibited both hypoxia-induced transactivation of the HIF-1 reporter gene and IL-1 secretion from transfected astrocytes. Collectively, the evidence suggests that the transcriptional activation of IL-1 beta in astrocytes exposed to hypoxia occurs via HIF-1. (c) 2006 Elsevier B.V All rights reserved.